SRF Live Discussion Series: Anticipating the DSM-V
Schizophrenia Research Forum is presenting a series of live discussions focusing on areas of contention within the evolution of the Diagnostic and Statistical Manual (DSM) psychotic disorders area.

The discussion on 15 December 2009 was led by Stephan Heckers of Vanderbilt University and Rajiv Tandon of the University of Florida, and addressed the value of the schizoaffective diagnosis. Please read the backgrounder below and the article by Heckers mentioned therein. Then add your comments.

Emil Kraepelin divided the psychoses into non-affective (dementia praecox, later schizophrenia) and affective (manic depression, later bipolar disorder) types. This dichotomy continues to this day in diagnostic manuals (see SRF related Live Discussion). As discussed by Stephan Heckers in the background text below, Jacob Kasanin introduced the diagnosis schizoaffective disorder in 1933 (Kasanin, 1933) to describe patients with both prominent psychotic and affective symptoms. The diagnosis, with minor variations, has been part of the DSM since its first edition in 1952.

“However, the current DSM-IV-TR diagnosis of schizoaffective disorder is not reliable and is of limited clinical utility,” Heckers writes. He traces the evolution of the current schizoaffective disorder diagnosis in the DSM and reviews options for revision (see list of options below, courtesy of S. Heckers). Some modifications are minor, whereas others are more radical. Do we have enough evidence to remove the diagnosis from the DSM? What does a revision of the diagnosis schizoaffective disorder mean for the more fundamental dichotomy of affective and non-affective psychoses? We invite your preliminary commentary on the options presented.

Schizoaffective Disorder Considerations for DSM-VAlthough dementia praecox or schizophrenia has been considered a unique disease entity for the past century, its definitions and boundaries have varied over this period. The relationship between schizophrenia and the major mood disorders (bipolar disorder and major depressive disorder) has been a topic of much ambiguity with ill-defined and fluctuating boundaries. Schizoaffective disorder has been at the interface of the boundary between schizophrenia and the major mood disorders, and opinions about its nature vary considerably. The following are four characterizations of schizoaffective disorder:

1. A unique condition clearly demarcated from both schizophrenia and major mood disorders
2. A subtype of schizophrenia
3. A subtype of major mood disorders with psychosis
4. Not a unique entity but an admixture of schizophrenia and major mood disorders that are difficult to differentiate

Despite its uncertain nature, schizoaffective disorder is widely diagnosed and is considered by clinicians to be a useful construct. On the other hand, its validity is questionable, with most data suggesting that patients diagnosed with this condition represent a mixture of those with schizophrenia and those with major mood disorder. Additionally, it has marginal reliability and low diagnostic stability. Given its perceived clinical utility in the context of poor reliability and validity, is it possible that eliminating it as a categorical entity but providing a dimensional approach toward measuring both psychotic and mood symptoms might provide for a more valid, reliable, and clinically useful construct? Alternatively, one could ask the question of whether or not schizoaffective disorder should be retained as a distinct entity but be better defined so that it can be more clearly discriminated from both schizophrenia and major mood disorders. These issues were considered by the DSM-V workgroup on schizophrenia and related psychotic disorders, and the second approach was selected; the proposed revisions are detailed in the Draft of proposed DSM-V modifications.

One of my professors taught me that the most important thing in creating effective psychiatric treatment is the diagnosis. While this point may be obvious, it becomes problematic when a diagnostic dilemma is brought to the foreground. The fact that there is a DSM-V position paper that questions the existence of one of the subgroups of schizophrenia is significant (Srivastava, 2009).

Before I comment on whether or not the diagnosis of schizoaffective disorder ought to be contained under the rubric of schizophrenias, mood disorders, or as an independent psychiatric disorder, it is useful to recap what constitutes a diagnosis. Clinical psychiatry continues to function through an exploratory model of descriptive symptoms, signs, and syndromes. A definitive diagnosis is exclusively clinical in nature. Considerable differences of opinion and conflicting viewpoints exist regarding whether a particular symptom in a given disorder is part of the disease or exists outside the realm of that disease, thus qualifying as a comorbid symptom. For example, many clinicians would refrain from a diagnosis of schizophrenia with OCD or GAD, and would be happy to consider these phenomena as part of the spectrum of the illness. Thus, our first problem is to be able to decide criteria for diagnosis. I don’t think the DSM-V is addressing this fundamental difficulty, and it may be the case that we require more evidence and phenomenological knowledge before we can create a definition and criteria for psychiatric diagnosis.

The question regarding whether or not schizoaffective disorder is a useful diagnosis entails an examination of whether or not SAD is indeed a sub-diagnosis of schizophrenia.

No one is surprised with this proposal as history repeats itself. Positioning of the schizoaffective disorder has been shifting from one end of the diagnostic spectrum to the other (Tsuang, 1979; Singh and Sachdeva, 1982). Jacob Kasanin (1933) originally proposed this group for atypical syndromes in terms of schizophrenia and mood disorder. In 1961 Leonard called it the “third psychosis,” retaining a similar description as Kasanin’s definition. The International Classification System of World Health Organization, ICD 9, subsumed it under schizophrenia. However, in the Research Diagnostic Criteria (RDC), SAD was kept as a separate entity. In the 1986 draft of the ICD 10, SAD was assigned to the affective disorder category, but in the final version of ICD 10, it was placed alongside the category of schizophrenic disorder. The idea of SAD as a separate entity continued within the DSM-III R; however, in DSM-IV, it again became a subgroup within schizophrenic disorders. The story continues.

The silently implied issue is that we are not talking about mood symptoms across schizophrenia. We are discussing whether there is a symptom cluster that is based on the current understanding of psychiatric illnesses that we can designate as schizoaffective disorder, and whether the strength of the clinical and research evidence suggests retaining SAD as a variety of schizophrenia.

We conducted a study in which we followed individuals diagnosed with schizoaffective disorder for two years. Our goal was to test the stability of the diagnosis, and we found that only 11 percent of patients retained the SAD diagnosis. The majority (72 percent) changed over to schizophrenia, and 17 percent changed to unipolar and bipolar mood disorder (Shrivastava and Rao, 1997). Several authors have written that SAD is an inconsistent syndrome as a diagnosis.

If we examine the available evidence of parameters of clinical course and outcome, neurochemistry, neuroimaging, genetics, and treatment response, which are normally the main parameters to consider a symptom-cluster or syndrome as a diagnosis, we find that schizoaffective disorder does not maintain an exclusive diagnostic entity on any of these parameters. There is some evidence of a neurochemistry parameter that is equivocal; however, neurochemical parameters are not considered to be very strong parameters.

There is no valid argument justifying the removal of SAD from the DSM-V. Its presence as a diagnostic category provides a scope of ambiguity and non-specificity in clinical practice. Research in the field of course and phenomenology of brief reactive psychosis, early psychosis, and schizophrenia spectrum disorder have provided enough evidence that mood symptoms exist and arise from common neurobiological basis, and the pathogenesis of schizoaffective disorder can be articulated along these lines. However, this again does not solve the problem. Leaders within the research community have the responsibility to provide a logical placement of schizoaffective disorder.

The philosophy driving the DSM-V is based on a movement toward a dimensional approach and away from a categorical system, which is highly comforting for those of us engaged in clinical work. Hopefully, the classification as domains of schizophrenia may be retained.

In my opinion, schizoaffective disorder would best be suited as an affective domain of schizophrenia.

The proposed discussion is fundamental as the clinical diagnosis imposes the therapeutic management and the orientation of the scientific research in the psychoses field.

When confronted with a possible case of schizoaffective disorder (SAD), the clinician has to make important decisions, often with profound consequences.
The background paper by Heckers (Heckers, 2009) highlights the difficulty of the longitudinal diagnosis due to the lack of reliable information and the doubtful accuracy of self-report, especially from a patient with psychosis. Consequently, the diagnosis is merely cross-sectional, based on clinical observation and interview, but necessary for the immediate therapeutic endeavor. Moreover, as it is well known, the context of the therapeutic decision does not simplify treatment choices, since the available therapies mostly comprise symptomatic medication and are not etiologically based. Practically, the clinician who needs to provide care for a patient with SAD has to answer questions like, Are the depressive symptoms substantial enough to add an antidepressant to the antipsychotics?” or Can the manic symptoms be controlled by antipsychotics only, or, Is a mood stabilizer (i.e., lithium, valproate) also necessary? Obviously, the decision is not trivial since the spectrum of adverse effects is exponentially complicated by the various pharmacological combinations.

In clinical practice, there are other aspects of the SAD diagnosis that require specific attention (e.g., substance abuse, increased suicidal risk). It is clear that clinicians need a way to describe the cohabitation between psychotic and affective/mood symptoms.

Tandon concludes his slidecast with the (Tandon, 2009) proposal that the DSM-V keep the SAD diagnosis with the amendment of the operational criteria and consequently the improving of diagnosis reliability. While this is a judicious approach, the issue of how one conceptualizes psychosis remains, along with the “compromise” diagnoses of SAD. Obviously, the leaders in the field who work on DSM-V still need to decide if the definition of psychosis should be based on the Kraepelinian dichotomy, or should be viewed on a “continuum,” or even better, as a mixture of symptomatic dimensions. From this angle, a redefinition of psychosis on a dimensional basis with diagnostic criteria adjusted for practical purposes might be helpful for clinicians and researchers. Some consistent symptomatic dimensions such as positive, negative, and disorganization (Bilder et al., 1985; Liddle et al., 1989) or negative, positive, cognitive, excitation, depression/anxiety (Lindenmayer et al., 1994; Von Knorring and Lindstrom, 1995; Radulescu, 2003) have emerged from factor analytical studies, with some variation due to the assessment instruments. In this respect, an affective dimension is distinguishable within the psychotic spectrum. However, it might be useful to remember that the affective dimension is complex and encompasses various phenomenological aspects that can align the dimension closer to the schizophrenic spectrum or to the mood disturbance spectrum. The affective domain may suffer qualitative changes manifested through affective incongruence/inadequacy, or affective ambivalence more characteristic of schizophrenia. Similarly, there could be quantitative changes in the direction of hypothymia/affective impoverishment (the affective flattening characteristic of the deficit syndrome described by Carpenter, 1994) or hyperthymia, with the exacerbation of affective tone toward the depressive or manic end. Similar fluctuations are described within perceptual or thought domains, which also contributes to the complexity of the clinical picture across these dimensions. Further complicating the diagnostic process, the weight of symptomatic dimensions may vary longitudinally for the same individual, so it might be useful to view psychosis in a broader manner—as a dynamic ensemble of intermixed symptomatic dimensions: perceptual, thought, affective, etc. While this would add an element of flexibility that could be useful to clinicians, it would constrain clinicians to a careful evaluation of each symptomatic dimension with clear implications for the therapeutic decision. From this point of view, the cross-sectional SAD diagnosis might be equivalent to psychotic disorder with co-dominance of perceptual (hallucinations), thought (delusions), affective (depression) disturbances.

The dimensional approach might have important implications for research, too. It’s noted in Heckers’s paper (Heckers, 2009) that within categorical diagnosis, scientists usually group SAD with schizophrenia. This implies that in terms of biology, SAD is actually viewed as a type of schizophrenia, which raises concern. It is well known that within the biological etiology of psychosis, scientists have a justified preference to focus on endophenotypes, not on clinical symptoms (Meyer-Lindenberg and Weinberger 2006). However, here intervenes a paradoxical situation: In the procrustean manner imposed by the DSM criteria, clinicians use diagnostic labels that subsequently are used in research for grouping psychiatric patients and comparing these groups with normal individuals or unaffected relatives with respect to endophenotypes. According to criteria proposed by Gottesman and Gould (2003), the endophenotype (aka intermediate phenotype or vulnerability marker) is associated with the illness, is heritable, state-independent, and within families segregates with the illness. It is also suggested that an endophenotype, less complex than clinical phenotype, is closer to the biological determinants and correlated with the illness, suggesting a linear relationship. However, is this the case, especially for SAD, which has a poor validity? Is it, therefore, justifiable to group it with schizophrenia? As it was specified in Heckers’s (2009) paper and in Shrivastava’s comment, longitudinal studies show that a substantial proportion of SAD-diagnosed individuals will evolve similarly to individuals diagnosed with schizophrenia. However, some will follow the path of individuals diagnosed with a form of mood disorder. While this is the case, could one assume that the relationship between any schizophrenia endophenotype and SAD is the same as the relationship between that endophenotype and the classical schizophrenia? This question is really important in research nowadays, when studies of great amplitude (especially in psychiatric genetics) are ongoing and the homogeneity of diagnosis is a prerequisite of reliable results.
Maybe a dimensional approach could be one way to better group the affected subjects. Working with dimensions might help us discern which brain circuitry is more severely affected, and consequently, which endophenotypes are suitable for group comparisons. One might even attempt to assess which symptomatic dimension could have an endophenotype value. In this respect the cognitive dimension has already been evaluated as an endophenotype specific to schizophrenia (Goldberg et al., 1995).

In conclusion, as a clinician, I hope that the DSM-V will offer a more flexible diagnostic guide, with room for a dimensional approach to evaluating psychosis. In the particular case of the SAD diagnosis, even if it will remain in use, one could specify that it be used in a provisional manner until longitudinal validation is well documented. As a researcher, I would operate more comfortably with symptomatic dimensions that might be closer to endophenotypes and the subjacent biology.

Contrary to most other areas of investigative medicine, the term “diagnosis” in psychiatry does not define the etiology of an illness but rather specifies a set of observable behavioral phenomena that arise as a result of some presumably common, yet unidentified etiological factor. Thus, the utility of a psychiatric diagnosis depends upon how well it lends itself to the discovery of these etiological factors. From a research perspective, then, it seems that the primary question that needs to be addressed is whether or not a change in the diagnostic criteria for schizoaffective disorder, by either including it as a subtype of schizophrenia or the affective disorders or by providing clearer diagnostic criteria, will enhance our ability to identify the pathophysiological mechanisms responsible for the symptoms associated with the diagnosis.

Presently, there is a paucity of data on the molecular mechanisms that might differentiate schizoaffective disorder from other psychotic and affective disorders. In molecular genetic studies, schizoaffective cases may be viewed as problematic and excluded from genetic analyses, or, more commonly, are combined with either a predominantly psychotic group or a predominantly affective group. The few studies that have treated schizoaffective disorder as a separate diagnostic group, however, have produced some intriguing results.

To date, a single linkage study of schizoaffective disorder has been reported with findings indicating a significant linkage peak near the gene encoding disrupted in schizophrenia 1 (DISC1) at chromosome 1q42 (Hashmere et al., 2005). Data from genetic association studies has provided further support for the relation between DISC1 and schizoaffective disorder. For example, Hodgkinson and colleagues (2004) identified several single nucleotide polymorphisms (SNPs) in DISC1 that were associated with schizoaffective disorder but not with schizophrenia or bipolar disorder. Moreover, other variants were associated with risk for schizophrenia and bipolar disorder but not schizoaffective disorder, suggesting that genetic heterogeneity at this locus may function to alter the phenotypic expression of psychiatric illness. To our knowledge, only a single study has compared the frequencies of a single risk locus across diagnostic categories ranging from purely affective to purely psychotic disorders. Lencz et al. (2009) compared the frequencies of a BDNF risk haplotype across diagnostic groups including schizophrenia, schizoaffective disorder, affective disorders, and healthy individuals, and found that the frequency of the risk haplotype in the schizoaffective disorder group was similar to other affective disorders, and dissimilar from schizophrenia and healthy controls. Taken together, data derived from these molecular genetic studies, although exceedingly limited, suggest that at the molecular genetic level there is both overlap and independence amongst these diagnostic groups.

At the clinical level, the topic “Do we need schizoaffective disorder?” is an empirical question which we are currently not well equipped to answer. Specifically, while the diagnosis of schizoaffective disorder requires a longitudinal clinical assessment, most of the data seeking to validate the diagnosis rely on cross-sectional rather than longitudinal data. To date, the limited data that are available to address the longitudinal course of schizoaffective disorder indicate that the clinical outcomes for these patients are substantially worse than the outcomes observed in patients with psychotic affective disorder and substantially better than the outcomes observed in schizophrenia (Harrow et al., 2000; Jäger et al., 2004). Despite our growing understanding of the factors mediating clinical outcomes, however, there are few data seeking to elucidate differences in these factors amongst these diagnostic groups.

Our group has recently completed an analysis of a large cohort of patients (N = 993) in which we tested longitudinal hypotheses about the cognitive and clinical differences between the aforementioned patient groups. Among the most striking findings in these analyses was that schizoaffective disorder patients appear to undergo a more severe cognitive decline than either patients with schizophrenia or psychotic bipolar disorder. These findings were somewhat surprising, given previous reports of the relation between impaired cognitive function and worse clinical outcomes (Harvey et al., 2009). However, the most significant symptom variable that separated these diagnostic groups, which is also strongly correlated with clinical outcome (Leung et al., 2008), was the negative symptom cluster. Specifically, the schizoaffective disorder group showed levels of negative symptoms intermediate to those observed in the schizophrenia and psychotic bipolar disorder group. Moreover, we have found that many of the demographic characteristics of patients with schizoaffective disorder are more consistent with those observed in the psychotic bipolar disorder, while many of the clinical characteristics observed are more consistent with the schizophrenia diagnostic group. Thus, rather than providing direct support for the independence of schizoaffective disorder from either schizophrenia or psychotic affective disorders, these data directly challenge the assignment of the schizoaffective diagnosis to a mere subtype of either schizophrenia or the affective psychoses.

The convergence of the molecular genetic and clinical data currently available seems to provide little evidence for either abolishing the schizoaffective disorder diagnosis or subsuming it under the schizophrenia or psychotic affective disorder clusters. Therefore, we would argue in favor of revising the diagnostic criteria for schizoaffective disorder. This revision would theoretically provide a better phenotype for the type of longitudinal studies that will be required to validate or remove the diagnosis from future editions of the DSM.

The diagnosis of schizoaffective disorder may be either too broad or redundant as it stands. It could be too broad as major depression may be a comorbidity of schizophrenia, similar to comorbid anxiety disorders, thus requiring the narrowing down of schizoaffective disorder to schizophrenia with bipolar disorder. It may be redundant, as if the century-old assumption, inherited from Kraepelin, that dementia praecox (schizophrenia) and manic-depressive illness (bipolar disorder) are mutually exclusive, is not endorsed anymore; bipolar disorder can also be viewed as a comorbidity of schizophrenia. Research on such comorbidity possibilities is needed in order to determine the nosological status and value of schizoaffective disorder.

I am afraid that due to access difficulties I have read the abstract only. I am aware that it has been suggested that the schizoaffective category be abolished. I do not think this would be helpful at the present time. I have some comments:

1. The difficulty with poor reliability comes in large part from the very "narrow" definition currently used and common interpretation of "schizoaffective" as being used only when a case cannot be fitted to either schizophrenia or mood disorder categories (i.e., starting with the assumption of a dichotomy). A broader definition would be more reliable, stable—and useful.

2. Incorporating dimensional measures to sit alongside categories is an excellent idea and will obviously help with recognition of overlapping psychosis and mood features.

3. However, abolishing the schizoaffective category whilst retaining mood and schizophrenia categories would send a completely inappropriate message that would reinforce the idea of a dichotomy when we really need to be thinking about clinical spectra.

4. Accumulating genetic data suggest that there may be particular value in recognizing, at least for genetic investigations, cases with a rich mix of schizophrenia-like psychotic and bipolar mood features.

5. Making major changes to classification categories in the absence of compelling reasons would change risks of untoward consequences (financial, training, logistics, time, and confusion). In the face of evidence that a category may be useful, it makes no sense at all.

6. "Schizoaffective” cases vary enormously in the nature of symptomatology and their temporal relationship. Definitions of schizoaffective should be applicable longitudinally.

Mike Owen, Mick O'Donovan, and I have written both data and review/opinion papers on this topic. Some relevant papers are listed below.

As noted by Marneros, schizoaffective disorder remains “a...
Read more

As noted by Marneros, schizoaffective disorder remains “a nosological nuisance but a clinical reality” (Marneros, 2003). It is a category that lacks reliability and is used with highly varying frequency in the field. Though we use the diagnosis only infrequently here at Johns Hopkins, it is applied to 20 percent or more of admissions at other academic and non-academic psychiatric inpatient units. Since the higher rate is the norm, removing the diagnoses from DSM-V would leave many clinicians in the lurch, particularly since some of the alternative proposals (e.g., the use of dimensions) might increase reliability, but are, as yet, untested constructs of uncertain clinical utility. While the use of dimensional measures (particularly in complement to categorical constructs) may turn out to have greater validity and/or clinical utility, we believe that, at present, this is a question that must be addressed by empirical research before it can be implemented in DSM-V. To implement such a major change without a substantial empirical database could increase confusion without adding clinical value. At the same time, it is imperative that researchers consider alternatives to DSM-IV SA with regard to biological origins (i.e., validity) and clinical utility. This will be an important but daunting task that is unlikely to be accomplished by the DSM-V field trials.

Hence, for the time being, our suggestion is to leave the category largely as it is, though perhaps with the minor changes being proposed by Drs. Heckers and Tandon that are likely to improve the clarity of the diagnostic construct. In strong agreement with the original text in DSM-III (American Psychiatric Association, 1980; p. 202), however, we urge that clinicians use the schizoaffective disorder category only sparingly, and with the knowledge that it is an unreliable and unstable diagnosis that requires ongoing re-evaluation.

The Mood Disorders Committee in general currently supports...
Read more

The Mood Disorders Committee in general currently supports the retention of the schizoaffective diagnosis in DSM-V. One basis for this is the very frequent use of this diagnosis in the Medicaid and Privately Insured Data Base published June 23, 2009, by Mark Olfson, MD, MPH. A study of first-episode psychoses by Mauricie Tohen found that these patients, initially diagnosed Psychosis NOS, when followed, showed the highest switch in diagnosis to schizoaffective disorder than any other diagnosis.

My own personal take is based on the study by Andreasen et al. (1987) from the Collaborative Depression Study which showed that the relatives of patients with schizoaffective disorder, depressed, had a preponderance of relatives with schizophrenia, while the relatives of patients with schizoaffective disorder, bipolar type, had a preponderance of bipolar I disorder. This suggests to me a Solomonesque solution of dividing the baby, schizoaffective disorder, in half, the schizoaffective bipolars being diagnosed as bipolar I with psychosis, and the schizoaffective depressed being diagnosed as schizophrenia with major depression.